Angiotensin II Induces Aortic Rupture and Dissection in Osteoprotegerin-Deficient Mice.

Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)-induced hypertension. Methods and Results Mortality was higher (P<0.0001 by log-rank test) in 8-week-old male homozygotes of osteoprotegerin gene-knockout mice given subcutaneous administration of Ang II for 28 days, with an incidence of 21% fatal aortic rupture and 23% aortic dissection, than in age-matched wild-type mice. Ang II-infused aorta of wild-type mice showed that osteoprotegerin immunoreactivity was present with proteoglycan. The absence of osteoprotegerin was associated with decreased medial and adventitial thickness and increased numbers of elastin breaks as well as with increased periostin expression and soluble receptor activator of nuclear factor-kappa B ligand concentrations. PEGylated human recombinant osteoprotegerin administration decreased all-cause mortality (P<0.001 by log-rank test), the incidence of fatal aortic rupture (P=0.08), and aortic dissection (P<0.001) with decreasing numbers of elastin breaks, periostin expressions, and soluble receptor activator of nuclear factor-kappa B ligand concentrations in Ang II-infused osteoprotegerin gene-knockout mice. Conclusions These data suggest that osteoprotegerin protects against aortic rupture and dissection in Ang II-induced hypertension by inhibiting receptor activator of nuclear factor-kappa B ligand activity and periostin expression.

Development of a novel human adrenomedullin derivative: human serum albumin-conjugated adrenomedullin.

Adrenomedullin is a biologically active peptide with multiple functions. Here, we have developed a novel human serum albumin-adrenomedullin (HSA-AM) conjugate, which was synthesized by the covalent attachment of a maleimide derivative of adrenomedullin to the 34th cysteine residue of HSA via a linker. Denaturing gel electrophoresis and western blotting for HSA-AM yielded a single band with adrenomedullin immunoreactivity at the position corresponding to a molecular weight (MW) of 73 kDa. Following gel-filtration chromatography, the purified HSA-AM showed a single main peak corresponding with an MW of 73 kDa, indicating that HSA-AM is a monomer. Both adrenomedullin and HSA-AM stimulated the intracellular accumulation of cyclic AMP (cAMP) in HEK-293 cells stably expressing the adrenomedullin 1 receptor. The pEC50 values for adrenomedullin and HSA-AM were 8.660 and 7.208 (equivalent to 2.19 and 61.9 nM as EC50), respectively. The bioavailability of HSA-AM compared with that of adrenomedullin was much improved after subcutaneous administration in the rat, which was probably due to the superior resistance of HSA-AM towards endogenous proteases and its reduced clearance from the blood. HSA-AM may be a promising drug candidate for clinical application.

Natriuretic peptides and neprilysin inhibition in hypertension and hypertensive organ damage.

The family of natriuretic peptides (NPs) discovered in mammalian tissues including cardiac atrium and brain consists of three members, namely, atrial, B- and C-type natriuretic peptides (ANP, BNP, CNP). Since the discovery, basic and clinical studies have been vigorously performed to explore the biological functions and pathophysiological roles of NPs in a wide range of diseases including hypertension and heart failure. These studies revealed that ANP and BNP are hormones secreted from the heart into the blood stream in response to pre- or after-load, counteracting blood pressure (BP) elevation and fluid retention through specific receptors. Meanwhile, CNP was found to be produced by the vascular endothelium, acting as a local mediator potentially serving protective functions for the blood vessels. Because NPs not only exert blood pressure lowering actions but also alleviate hypertensive organ damage, attempts have been made to develop therapeutic agents for hypertension by utilizing this family of NPs. One strategy is to inhibit neprilysin, an enzyme degrading NPs, thereby enhancing the actions of endogenous peptides. Recently, a dual inhibitor of angiotensin receptor-neprilysin was approved for heart failure, and neprilysin inhibition has also been shown to be beneficial in treating patients with hypertension. This review summarizes the roles of NPs in regulating BP, with special references to hypertension and hypertensive organ damage, and discusses the therapeutic implications of neprilysin inhibition.

Adrenomedullin: Continuing to explore cardioprotection.

Adrenomedullin (AM), a peptide isolated from an extract of human pheochromocytoma, comprises 52 amino acids with an intramolecular disulfide bond and amidation at the carboxy-terminus. AM is present in various tissues and organs in rodents and humans, including the heart. The peptide concentration increases with cardiac hypertrophy, acute myocardial infarction, and overt heart failure in the plasma and the myocardium. The principal function of AM in the cardiovascular system is the regulation of the vascular tone by vasodilation and natriuresis via cyclic adenosine monophosphate-dependent or -independent mechanism. In addition, AM may possess unique properties that inhibit aldosterone secretion, oxidative stress, apoptosis, and stimulation of angiogenesis, resulting in the protection of the structure and function of the heart. The AM receptor comprises a complex between calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein (RAMP) 2 or 3, and the AM-CLR/RAMP2 system is essential for heart development during embryogenesis. Small-scale clinical trials have proven the efficacy and safety of recombinant AM peptide therapy for heart failure. Gene delivery and a modified AM peptide that prolongs the half-life of the native peptide could be an innovative method to improve the efficacy and benefit of AM in clinical settings. In this review, we focus on the pathophysiological roles of AM and its receptor system in the heart and describe the advances in AM and proAM-derived peptides as diagnostic biomarkers as well as the therapeutic application of AM and modified AM for cardioprotection.

Angiotensin II Stimulation of Cardiac Hypertrophy and Functional Decompensation in Osteoprotegerin-Deficient Mice.

Circulating and myocardial expressions of receptor activator of nuclear factor-κb ligand and osteoprotegerin are activated in heart failure; however, it remains to be determined their pathophysiological roles on left ventricular structure and function in interaction with renin-angiotensin system. We conducted experiments using 8-week-old osteoprotegerin(-/-) mice and receptor activator of nuclear factor-κb ligand-transgenic mice to assess whether they affect the angiotensin II-induced left ventricular remodeling. Subcutaneous infusion of angiotensin II to osteoprotegerin(-/-) mice progressed the eccentric hypertrophy, resulting in left ventricular systolic dysfunction for 28 days, and this was comparable with wild-type mice, showing concentric hypertrophy, irrespective of equivalent elevation of systolic blood pressure. The structural alteration was associated with reduced interstitial fibrosis, decreased procollagen α1 and syndecan-1 expressions, and the increased number of apoptotic cells in the left ventricle, compared with wild-type mice. In contrast, angiotensin II infusion to the receptor activator of nuclear factor-κb ligand-transgenic mice revealed the concentric hypertrophy with preserved systolic contractile function. Intraperitoneal administration of human recombinant osteoprotegerin, but not subcutaneous injection of anti-receptor activator of nuclear factor-κb ligand antibody, to the angiotensin II-infused osteoprotegerin(-/-) mice for 28 days ameliorated the progression of heart failure without affecting systolic blood pressure. These results underscore the biological activity of osteoprotegerin in preserving myocardial structure and function during the angiotensin II-induced cardiac hypertrophy, independent of receptor activator of nuclear factor-κb ligand activity. In addition, the antiapoptotic and profibrotic actions of osteoprotegerin that emerged from our data might be involved in the mechanisms.

Bench-to-bedside pharmacology of adrenomedullin.

The bioactive peptide adrenomedullin (AM) exerts pleiotropic actions in various organs and tissues. In the heart, AM has an inhibitory effect on ventricular remodeling, suppressing cardiomyocyte hypertrophy and the proliferation of cardiac fibroblasts. This pharmacological property was shown not only in rat models of acute myocardial infarction, but also clinically in patients with this cardiac disease. An originally characterized feature of AM was a potent vasodilatory effect, but this peptide was found to be important for vascular integrity and angiogenesis. AM-induced angiogenesis is involved in tumor growth, while AM inhibits apoptosis of some types of tumor cell. A unique pharmacological property is anti-inflammatory activity, which has been characterized in sepsis and inflammatory bowel diseases; thus, there is an ongoing clinical trial to test the efficacy of AM for patients with intractable ulcerative colitis. These activities are assumed to be mediated via the specific receptor formed by calcitonin receptor-like receptor and receptor activity-modifying protein 2 or 3, while some questions remain to be answered about the molecular mechanisms of this signal transduction system. Taking these findings together, AM is a bioactive peptide with pleiotropic effects, with potential as a therapeutic tool for a wide range of human diseases from myocardial infarction to malignant tumors or inflammatory bowel diseases.

Biological properties of adrenomedullin conjugated with polyethylene glycol.

Adrenomedullin (AM) is a vasodilator peptide with pleiotropic effects, including cardiovascular protection and anti-inflammation. Because of these beneficial effects, AM appears to be a promising therapeutic tool for human diseases, while intravenous injection of AM stimulates sympathetic nerve activity due to short-acting potent vasodilation, resulting in increased heart rate and renin secretion. To lessen these acute reactions, we conjugated the N-terminal of human AM peptide with polyethylene glycol (PEG), and examined the biological properties of PEGylated AM in the present study. PEGylated AM stimulated cAMP production, an intracellular second messenger of AM, in cultured human embryonic kidney cells expressing a specific AM receptor in a dose-dependent manner, as did native human AM. The pEC50 value of PEGylated AM was lower than human AM, but no difference was noted in maximum response (Emax) between the PEGylated and native peptides. Intravenous bolus injection of 10nmol/kg PEGylated AM lowered blood pressure in anesthetized rats, but the acute reduction became significantly smaller by PEGylation as compared with native AM. Plasma half-life of PEGylated AM was significantly longer than native AM both in the first and second phases in rats. In summary, N-terminal PEGylated AM stimulated cAMP production in vitro, showing lessened acute hypotensive action and a prolonged plasma half-life in comparison with native AM peptide in vivo.

Big angiotensin-25: a novel glycosylated angiotensin-related peptide isolated from human urine.

The renin-angiotensin system (RAS), including angiotensin II (Ang II), plays an important role in the regulation of blood pressure and body fluid balance. Consequently, the RAS has emerged as a key target for treatment of kidney and cardiovascular disease. In a search for bioactive peptides using an antibody against the N-terminal portion of Ang II, we identified and characterized a novel angiotensin-related peptide from human urine as a major molecular form. We named the peptide Big angiotensin-25 (Bang-25) because it consists of 25 amino acids with a glycosyl chain and added cysteine. Bang-25 is rapidly cleaved by chymase to Ang II, but is resistant to cleavage by renin. The peptide is abundant in human urine and is present in a wide range of organs and tissues. In particular, immunostaining of Bang-25 in the kidney is specifically localized to podocytes. Although the physiological function of Bang-25 remains uncertain, our findings suggest it is processed from angiotensinogen and may represent an alternative, renin-independent path for Ang II synthesis in tissue.

Functions of third extracellular loop and helix 8 of Family B GPCRs complexed with RAMPs and characteristics of their receptor trafficking.

At least one of three receptor activity-modifying proteins (RAMP1, RAMP2 and RAMP3) can interact with 10 G protein-coupled receptors (GPCRs; nine Family B GPCRs and a Family C GPCR). All three RAMPs interact with the calcitonin (CT) receptor (CTR), the CTR-like receptor (CLR), the vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) 1 (VPAC1) and the VPAC2 receptor, which are all Family B GPCRs. Three RAMPs enable CTR to function as three heterodimeric receptors for amylin, which is a feeding suppression peptide. These RAMPs also transport the CLR to the cell surface, where they function as a CT gene-related peptide (CGRP) receptor (CLR/RAMP1 heterodimer) and two adrenomedullin (AM) receptors (CLR/RAMP2 and CLR/RAMP3 heterodimers). CGRP and AM are potent hypotensive peptides that exert powerful protective effects against multi-organ damage. We recently reported that the third extracellular loop (ECL3) of CLR governs the activation of AM, but not CGRP, signaling in the three CLR/RAMP heterodimers. Furthermore, we showed that in the presence of RAMP2, the eighth helix (helix 8) in the proximal portion of the cytoplasmic C-terminal tail of the CLR, which is thought to be present in all family B GPCRs, participates in receptor signaling. In addition, we demonstrated that overexpression of GPCR kinase (GRK) 2, GRK3 and GRK4 enhances the AM-induced internalization of the CLR/RAMP2 heterodimer. In this review, we describe these studies and consider their implications for other Family B GPCRs that can interact with RAMPs.

Sarcoidosis manifesting as cardiac sarcoidosis and massive splenomegaly.

Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. We report an unusual case of sarcoidosis in a woman presenting with cardiac sarcoidosis and massive splenomegaly with a familial history of cardiac sarcoidosis. Cardiac sarcoidosis was diagnosed based on electrocardiogram, echocardiogram, 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG-PET) and skin histological findings. We performed splenectomy to rule out malignant lymphoma, and histological findings confirmed sarcoidosis. After splenectomy, we initiated prednisolone therapy. After 20 months of diagnosis, she was symptom free. Echocardiography and 18F-FDG-PET may be a key diagnostic tool and prednisolone therapy may be safe, effective, and feasible for cardiac sarcoidosis.

The third extracellular loop of the human calcitonin receptor-like receptor is crucial for the activation of adrenomedullin signalling.

BACKGROUND AND PURPOSE: The extracellular loops (ECLs) in Family A GPCRs are important for ligand binding and receptor activation, but little is known about the function of Family B GPCR ECLs, especially ECL3. Calcitonin receptor-like receptor (CLR), a Family B GPCR, functions as a calcitonin gene-related peptide (CGRP) and an adrenomedullin (AM) receptor in association with three receptor activity-modifying proteins (RAMPs). Here, we examined the function of the ECL3 of human CLR within the CGRP and AM receptors. EXPERIMENTAL APPROACH: A CLR ECL3 chimera, in which the ECL3 of CLR was substituted with that of VPAC2 (a Family B GPCR that is unable to interact with RAMPs), and CLR ECL3 point mutants were constructed and transiently transfected into HEK-293 cells along with each RAMP. Cell-surface expression of each receptor complex was then measured by flow cytometry; [(125) I]-CGRP and [(125) I]-AM binding and intracellular cAMP accumulation were also measured. KEY RESULTS: Co-expression of the CLR ECL3 chimera with RAMP2 or RAMP3 led to significant reductions in the induction of cAMP signalling by AM, but CGRP signalling was barely affected, despite normal cell-surface expression of the receptors and normal [(125) I]-AM binding. The chimera had significantly decreased AM, but not CGRP, responses in the presence of RAMP1. Not all CLR ECL3 mutants supported these findings. CONCLUSIONS AND IMPLICATIONS: The human CLR ECL3 is crucial for AM-induced cAMP responses via three CLR/RAMP heterodimers, and activation of these heterodimers probably relies on AM-induced conformational changes. This study provides a clue to the molecular basis of the activation of RAMP-based Family B GPCRs.

Identification of the endogenous cysteine-rich peptide trissin, a ligand for an orphan G protein-coupled receptor in Drosophila.

There are many orphan G protein-coupled receptors (GPCRs), for which ligands have not yet been identified, in both vertebrates and invertebrates, such as Drosophila melanogaster. Identification of their cognate ligands is critical for understanding the function and regulation of such GPCRs. Indeed, the discovery of bioactive peptides that bind GPCRs has enhanced our understanding of mechanisms underlying many physiological processes. Here, we identified an endogenous ligand of the Drosophila orphan GPCR, CG34381. The purified ligand is a peptide comprised of 28 amino acids with three intrachain disulfide bonds. The preprotein is coded for by gene CG14871. We designated the cysteine-rich peptide "trissin" (it means for triple S-S bonds) and characterized the structure of intrachain disulfide bonds formation in a synthetic trissin peptide. Because the expression of trissin and its receptor is reported to predominantly localize to the brain and thoracicoabdominal ganglion, trissin is expected to behave as a neuropeptide. The discovery of trissin provides an important lead to aid our understanding of cysteine-rich peptides and their functional interaction with GPCRs.

Clinical features and outcomes of eosinophilic myocarditis patients treated with prednisolone at a single institution over a 27-year period.

BACKGROUND: Eosinophilic myocarditis is a rare clinical entity characterized by eosinophilia and myocardial inflammation with infiltrating eosinophils. The prognosis of patients with eosinophilic myocarditis is difficult to determine due the disease's rarity and varied causes; consequently, standard treatment has not been established. OBJECTIVE: To elucidate the clinical characteristics and treatment outcome of eosinophilic myocarditis, we retrospectively studied 7 patients fulfilling the criteria of the Japanese Circulation Society for eosinophilic myocarditis from among 64 patients admitted to our institution with eosinophilia over a 27-year period. RESULTS: The patients' ages at diagnosis ranged from 36 to 83 years (median: 52 years). The etiologies of the eosinophilic myocarditis were found to be idiopathic (3 patients), Churg-Strauss syndrome (2 patients), parasitic infection (1 patient) and chronic eosinophilic leukemia (CEL) (1 patient). In addition to treatment for the underlying disease, we also administered prednisolone at a dose appropriate to the disease severity (6 of 7 patients). The patient who was diagnosed with a parasitic infection was treated only with albendazole, because eosinophilic myocarditis was mild. The patient with CEL was positive for the FIP1 L1-PDGFRα fusion gene and was treated with imatinib. Eosinophilic cationic protein was a useful marker for assessing disease activity and treatment efficacy. At the end of the study, of the seven patients treated, six were alive (86%), giving a mean survival time of 37 ± 40 months (mean ± SD). CONCLUSION: Because eosinophilic myocarditis has various etiologies, it is essential to identify the etiology of the underlying disease. In the majority of eosinophilic myocarditis patients, administration of prednisolone may be an effective therapeutic modality producing a good outcome.

Function of the cytoplasmic tail of human calcitonin receptor-like receptor in complex with receptor activity-modifying protein 2.

Receptor activity-modifying protein 2 (RAMP2) enables calcitonin receptor-like receptor (CRLR) to form an adrenomedullin (AM)-specific receptor. Here we investigated the function of the cytoplasmic C-terminal tail (C-tail) of human (h)CRLR by co-transfecting its C-terminal mutants into HEK-293 cells stably expressing hRAMP2. Deleting the C-tail from CRLR disrupted AM-evoked cAMP production or receptor internalization, but did not affect [(125)I]AM binding. We found that CRLR residues 428-439 are required for AM-evoked cAMP production, though deleting this region had little effect on receptor internalization. Moreover, pretreatment with pertussis toxin (100ng/mL) led to significant increases in AM-induced cAMP production via wild-type CRLR/RAMP2 complexes. This effect was canceled by deleting CRLR residues 454-457, suggesting Gi couples to this region. Flow cytometric analysis revealed that CRLR truncation mutants lacking residues in the Ser/Thr-rich region extending from Ser(449) to Ser(467) were unable to undergo AM-induced receptor internalization and, in contrast to the effect on wild-type CRLR, overexpression of GPCR kinases-2, -3 and -4 failed to promote internalization of CRLR mutants lacking residues 449-467. Thus, the hCRLR C-tail is crucial for AM-evoked cAMP production and internalization of the CRLR/RAMP2, while the receptor internalization is dependent on the aforementioned GPCR kinases, but not Gs coupling.

Adrenomedullin in mast cells of abdominal aortic aneurysm.

OBJECTIVES: Produced by vascular walls, adrenomedullin (AM) exerts antifibrotic actions in the process of cardiovascular remodeling. The purpose of this study was to examine the pathophysiological role of AM in the development of human abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Immunohistochemical analyses revealed that vascular smooth muscle cells in the media were positive for AM in the early stage of atherosclerotic aorta. Intense immunoreactivity was observed in mast cells of the outer media and adventitia of AAA, and the number of mast cells was greater (p < 0.01) in AAA than in atherosclerotic aorta without any aneurysmal change. To determine the role of AM in mast cells, we examined cultured human mast cell leukemia line-1 (HMC-1) and fibroblasts isolated from AAA patients. Cultured HMC-1 cells were found to express preproAM gene and release AM peptide into the cultured media. When assessed by collagenase-sensitive [3H]proline incorporation and procollagen type I C-peptide secretion, collagen synthesis in co-culture of HMC-1 and the fibroblasts was reduced by 10(-6) mol/L synthetic AM, while conversely, it increased following blockade of the action of endogenous AM with 10 microg/mL anti-AM monoclonal antibody. CONCLUSION: The present study suggests an anti-fibrotic role for AM released from mast cells, providing new insight into the biological actions of mast cell-derived AM in the development of AAA.

Adrenomedullin: a protective factor for blood vessels.

Adrenomedullin (AM) is a vasodilator peptide having a wide range of biological actions such as reduction of oxidative stress and inhibition of endothelial cell apoptosis. The AM gene is expressed in vascular walls, and AM was found to be secreted from cultured vascular endothelial cells, smooth muscle cells, and adventitial fibroblasts. Plasma AM levels in patients with arteriosclerotic vascular diseases are elevated in possible association with the severity of the disease. When administered over a relatively short period, AM dilates blood vessels via an endothelium-dependent or independent mechanism. Experiments in vitro have shown that AM exerts multiple actions on cultured vascular cells, which are mostly protective or inhibitory against vascular damage and progression of arteriosclerosis. Either prolonged infusion or overexpression of AM suppressed intimal thickening, fatty streak formation, and perivascular hyperplasia in rodent models for vascular remodeling or atherosclerosis. Intimal thickening induced by periarterial cuff was more severe in AM gene-knockout mice than their littermates, suggesting a protective role for endogenous AM. Moreover, AM has recently been suggested to possess angiogenetic properties. Collectively, a body of evidence suggests that AM participates in the mechanism against progression of vascular damage and remodeling, thereby alleviating the ischemia of tissues and organs.

Effect of adrenomedullin administration on acetic acid-induced colitis in rats.

Adrenomedullin (AM) administered intracolonically ameliorated the severity of acetic acid-induced colonic ulceration in rats. Ulcers were induced by subserosal injection of acetic acid into the colon. AM-treated group was administered 0.25-1.0 microg of AM in 0.5 ml of saline intracolonically once a day; the control group received only saline. AM administration dose-dependently and significantly reduced the size of the ulcerative lesions, the associated edema, and the infiltration of the affected area by inflammatory cells. AM also reduced tissue levels of interleukin-6, but not interferon-gamma. AM reduces the severity of acetic acid-induced colitis in rats, probably by inhibiting the production and/or release of Th-2 cell-derived factors such as interleukin-6.

Beyond vasodilation: the antioxidant effect of adrenomedullin in Dahl salt-sensitive rat aorta.

We have investigated the antioxidant effect of adrenomedullin (AM) on endothelial function in the Dahl salt-sensitive (DS) rat hypertension model. Dahl salt-resistant (DR) and DS rats were fed an 8% NaCl diet. In addition, the DS rats were subcutaneously infused with either saline or recombinant human AM for 4 weeks. Although systolic blood pressures measured weekly in AM- and saline-infused rats did not significantly differ, aortic O2*- levels were significantly (P<0.01) higher in the latter. Likewise, both endothelial nitric oxide synthase (eNOS) mRNA and protein were significantly higher in saline-infused DS rats. Infusion of AM reduced both O2*- and eNOS expression to levels comparable to those seen in DR rats. AM infusion also upregulated the gene expression of guanosine-5'-triphosphate cyclohydrolase I and downregulated the expression of p22(phox), suggesting that AM increased the NOS coupling and bioavailability of NO. AM possesses significant antioxidant properties that improve endothelial function.

Atrial and brain natriuretic peptides as markers of cardiac load and volume retention in primary aldosteronism.

BACKGROUND: Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones with natriuretic and vasodilator actions. The present study was carried out to determine the natriuretic peptide that is closely related to cardiac load and volume retention in patients with primary aldosteronism (PA). METHODS: We examined 11 patients with PA due to aldosterone-producing adrenal adenoma before and after surgical resection. Plasma levels of ANP and BNP were measured by specific immunoradiometric assays, and total blood volume was determined by a plasma tracer method with (131)I-human albumin. RESULTS: Plasma levels of ANP and BNP were elevated in the PA patients compared with normotensive control subjects (P < .01), and the elevated ANP and BNP levels were reduced (P < .01) after adenoma resection. When analyzed with the pre- and postoperative data, a significant relationship was observed between mean blood pressure and plasma levels of ANP (r = 0.64, P < .01) and BNP (r = 0.58, P < .01). The BNP was significantly correlated with the SV1 + RV5 voltage (r = 0.65, P < .01) and with total blood volume (r = 0.57, P < .01), but this was not the case for ANP. CONCLUSION: The present results suggest that the plasma level of BNP is more closely related to cardiac load or volume status than ANP is, in patients with PA due to adrenal adenoma.

Adrenomedullin alleviates not only neointimal formation but also perivascular hyperplasia following arterial injury in rats.

Producing components of the extracellular matrix, the vascular adventitia has been recognized as an important modulator of the vascular remodeling process, which determines the vessel architecture. In this study, we examined the effect of the vasodilator peptide adrenomedullin on vascular remodeling induced by balloon injury of rat carotid arteries. Endothelial denudation with wall stretch by ballooning not only induced neointimal formation accompanied with a reduced ratio of the lumen to vessel area, but also increased the fibroblast number and collagen deposition in the adventitial layer. When compared with the saline infusion, intravenous adrenomedullin infusion at 200 ng/h for 14 days suppressed the neointimal formation (-33%, P=0.033), reversing the ratio of lumen to vessel ratio (P=0.030), without affecting systolic blood pressure. Moreover, the adrenomedullin infusion decreased the number of adventitial fibroblasts (-41%, P<0.001) and the collagen deposition (-36%, P=0.006) in the adventitial layer of the injured artery. In conclusion, the intravenous adrenomedullin infusion effectively attenuates vascular remodeling following the arterial injury via suppression of hyperplasia in the intima and adventitia, suggesting a potential of adrenomedullin as a therapeutic tool against vascular remodeling.